Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
  • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• This invention relates to a method for chiral inversion of optically pure or optically enriched mixtures of (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide and (R)-( ⁇ )-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (compounds of formulas (I) and (II) respectively).
• This racemate (III) serves as a useful intermediate for the preparation of optically pure (S)-( ⁇ )-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide (V) and (R)-(+)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide (formula VI), two more recently disclosed, single-enantiomer putative anti-epileptic drugs demonstrating improved biological properties (Benes, J. et al., J. Med. Chem., 42, 2582-2587 (1999)).
• the (S)-( ⁇ )-enantiomer (V) in particular has been shown to display a very favourable anti-convulsant profile.
• a key step in the synthesis of either of the optically pure individual acetate esters (V) or (VI) involves the resolution of racemic ( ⁇ )-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (III) into its individual, optically pure stereoisomers, (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (I) and (R)-( ⁇ )-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (II), which are the principal intermediates for synthesis of the enantiomerically pure acetates (V) and (VI).
• the Mitsunobu procedure should preferably involve the use of readily available solvents and reagents, and be operationally simple whilst affording good yields of chirally-inverted, esterified products. Additionally, it would be highly desirable for large-scale manufacturing purposes to develop the Mitsunobu inversion reaction so as to obtain the desired inverted products in high purity and yield through a significantly simplified purification process without resort to inconvenient and tedious purification by column chromatography over silica gel which is usually required to remove unwanted reagents and by-products associated with the Mitsunobu reaction, such as, for example, triphenylphosphine, triphenylphosphine oxide, disubstituted azodicarboxylate and reduced hydrazine-derivatives thereof.
• unwanted reagents and by-products associated with the Mitsunobu reaction such as, for example, triphenylphosphine, triphenylphosphine oxide, disubstituted azodicarboxylate
• the carboxylic acid nucleophile can be used in a 1.02-5 molar ratio with respect to the optically pure or enriched alcohol (I) or (II), but preferably in the range 1.05-2.2.
• the reaction is carried out using a redox combination of a tri-substituted phosphine and disubstituted azodicarboxylate.
• Typical phosphines which are useful in the reaction include tri-n-propylphosphine, tri-n-butylphosphine, triphenylphosphine, tri-o-tolylphosphine, diphenyl(2-pyridyl)phosphine, (4-dimethylamino)diphenylphosphine, tris(dimethylamino)phosphine and the like. If preferred, the tri-substituted phosphine can be supported on an inert polymer.
• Preferred disubstituted azodicarboxylates include dimethylazodicarboxylate, diethylazodicarboxylate, diisopropylazodicarboxylate, di-tert-butylazodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine and the like.
• the tri-substituted phosphine and disubstituted azodicarboxylate are both used in equimolar quantities with respect to the optically pure or enriched alcohol (I) or (II).
• the reaction can be run in a solvent which is inert under the reaction conditions, such as, for example, chlorinated solvents including dichloromethane, chloroform and carbon tetrachloride, aliphatic or cyclic ethers including diethyl ether, tetrahydrofuran and dioxane, amides including dimethylformamide and hydrocarbons including toluene and the like.
• a solvent which is inert under the reaction conditions
• the reaction can be carried out over a wide range of temperatures, from ⁇ 78° C. to the boiling point of the solvent used, but preferably in the range 0° C.-30° C.
• the inverted product is then recovered by filtration and, if preferred, can be further purified by slurrying or recrystallisation from suitable solvents, such as, for example, lower aliphatic alcohols such as methanol, ethanol or isopropanol, with or without addition of water, esters including ethyl acetate or isopropyl acetate or ketones including acetone and methyl ethyl ketone.
• suitable solvents such as, for example, lower aliphatic alcohols such as methanol, ethanol or isopropanol, with or without addition of water, esters including ethyl acetate or isopropyl acetate or ketones including acetone and methyl ethyl ketone.
• suitable solvents such as, for example, lower aliphatic alcohols such as methanol, ethanol or isopropanol, with or without addition of water, esters including ethyl acetate or isopropyl acetate or keto
• R 1 is hydrogen, alkyl, halogenalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, aryl or pyridyl;
• alkyl means a straight or branched hydrocarbon chain containing from 1 to 18 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms;
• halogen means fluorine, chlorine, bromine or iodine;
• cycloalkyl means an alicyclic saturated group with 3 to 6 carbon atoms, preferably 5 or 6 carbon atoms;
• aryl means an unsubstituted phenyl group or phenyl substituted by alkoxy, halogen or nitro group, said method comprising reacting optically enriched (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (II) with the corresponding carboxylic acid nu
• optically pure or optically-enriched mixtures of both (R)-( ⁇ )- and (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (III) can be inverted and esterified by the present invention, whereby the desired (R)-(+)- or (S)-( ⁇ )-stereoisomers of all of the above compounds may be produced.
• compositions comprising the compound itself, or the derivative, in combination with a pharmaceutically acceptable carrier.
• Such compositions have anticonvulsant properties and can be used in the treatment of some central and peripheral nervous system disorders, such as epilepsy.
• the expression “optically pure” is used to include compositions which have optical purity of at least 80%, preferably at least 90%, most preferably at least 95%.
• the upper limit on optical purity may be, for example, 100% or 99.5% or 99%.
• the expression “optically enriched” means that there is more of one stereoisomer than there is of another stereoisomer in the composition, and, in particular, preferably means that there is at least at least 1% more of one stereoisomer (the “optically enriched” stereoisomer) than there is of the other stereoisomer, i.e., that there is at least 50.5% of the “optically enriched” stereoisomer and up to 49.5% of the other stereoisomer.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pain & Pain Management (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Biomedical Technology (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 2004
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